Long-term outcomes of bictegravir/emtricitabine/tenofovir alafenamide as first-line therapy and as switch strategy in virologically suppressed persons with HIV: data from the ICONA cohort.

OBJECTIVES: To assess the effectiveness of bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) among people poorly represented in clinical trials and potentially at higher risk of suboptimal response to ART. METHODS: Observational cohort study on persons with HIV (PWH) enrolled in ICONA who started BIC/FTC/TAF as initial therapy or as switching regimen while virologically suppressed. Primary endpoint was time to treatment failure (TF): new AIDS/death or virological failure (VF) or discontinuation for toxicity/failure. Secondary endpoints were time to treatment discontinuation for toxicity (TDT) and to VF. Groups of interest were those aged >50 years, female sex, and advanced HIV disease at first ART start. Probability of the events overall and according to groups and adjusted HR for every endpoint were calculated by Kaplan-Meier curves and Cox regression models. RESULTS: Nine hundred and thirty-three ART-naive and 1655 ART-experienced PWH initiated BIC/FTC/TAF. Over a median follow-up of 69.8 weeks, 89 (9.6%) PWH at their first regimen experienced TF. PWH aged >50 years had 1.83-fold (95% CI: 1.19-2.83) higher risk of TF; PWH with advanced HIV disease had 2.21-fold (95% CI: 1.53-3.82) higher risk; there were no differences in TF according to sex.Over a median follow-up of 146.3 weeks, 109 (6.6%) out of 1655 switching PWH experienced TF; no differences were found in the risk of TF, TDT and VF according to groups of interest. CONCLUSIONS: Overall, BIC/FTC/TAF is well tolerated and virologically effective in the real-world scenario for ART-naive and -experienced PWH. Older ART-naive PWH and those with advanced HIV disease may respond less well as the burden of diseases might compromise treatment efficacy.

Influence of efavirenz and 8-hydroxy-efavirenz plasma levels on cognition and central nervous system side effects.

OBJECTIVES: To investigate whether efavirenz (EFV) or 8-hydroxy-EFV (8-OH-EFV) plasma levels are associated with neurocognitive impairment and central nervous system (CNS) side effects. METHODS: We conducted a cross-sectional analysis to explore the potential links between EFV/8-OH-EFV levels and cognitive performance or CNS-related side effects in patients screened within a randomized trial involving a switch from EFV to rilpivirine. The Mann-Whitney test was employed to compare drug levels in patients with or without cognitive impairment, depression, anxiety, sleep disorder or CNS symptoms. Additionally, Spearman's test was used to assess correlations between drug levels and test scores. RESULTS: Among 104 patients, neither EFV nor 8-OH-EFV levels were linked to cognitive impairment, although trends towards higher EFV levels were observed in those with impaired executive function (p = 0.055) and language performances (p = 0.021). On the other hand, elevated 8-OH-EFV levels, but not EFV levels, were associated with more CNS side effects (222 vs. 151 ng/mL, p = 0.027), depressive symptoms (247 vs. 164 ng/mL, p = 0.067) and sleep impairment (247 vs. 164 ng/mL, p = 0.078). Consistently, a trend towards a correlation between EFV levels and lower z-scores in executive function and motor function was observed, while 8-OH-EFV levels, but not EFV levels, were directly correlated with symptom scores. CONCLUSIONS: Higher levels of 8-OH-EFV were associated with CNS side effects, while EFV levels were only marginally associated with cognitive performance, thus suggesting that EFV and its metabolite may act differently in determining detrimental neurological effects.

The presence of resistance-associated mutations in reverse transcriptase gene is associated with cerebrospinal fluid HIV-1 escape: A multicentric retrospective analysis.

Higher risk of cerebrospinal fluid escape (CVE) has been associated with the use of specific antiretroviral (ARV) classes, such as protease inhibitors. We assessed whether archived resistance-associated mutations (RAMs) can mediate this relationship by identifying patients treated with incompletely active antiretroviral regimens. A retrospective multicentric study on 282 adult people with HIV on antiretroviral therapy (ART) and available historical plasma genotype resistance testing (HGRT) for reverse transcriptase (RT) and protease genes between 2001 and 2021. The odds ratio for demographic, clinic-, and ART-related variables and CVE was estimated by multivariable modeling. HGRT-adjusted central nervous system effectiveness penetration (CPE) score was computed in modeling the risk. Median age, plasma VL, and CD4 count were 49 years, <50 copies/mL, and 310 cells/µL. CVE was detected in 51 participants (17.0%). No difference in CVE prevalence was observed according to ART type, number of ARVs or ARV classes. Participants with CVE had more frequently plasma (52.9% vs. 32.1%, p = 0.005) and CSF RAMs in RT (n = 63, 57.1% vs. 28.6%, p = 0.029), but not in protease gene. The presence of plasma RAMs in RT associated with increased odds of CVE in adjusted analyses (aOR 3.9, p < 0.001) and in models restricted to plasma viral load ≤50 copies/mL (n = 202; aOR 4.3, p = 0.003). CVE risk decreased by 40% per each point increase in HGRT-adjusted CPE score in multivariable models (p < 0.001). Rather than the type of ARV classes or of ART regimens, functional mono or dual regimens caused by the presence of RAMs affecting ART components may explain the majority of cases of CVE.

EuCARE-hospitalised study protocol: a cohort study of patients hospitalised with COVID-19 in the EuCARE project.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19), can lead to hospitalisation, particularly in elderly, immunocompromised, and non-vaccinated or partially vaccinated individuals. Although vaccination provides protection, the duration of this protection wanes over time. Additional doses can restore immunity, but the influence of viral variants, specific sequences, and vaccine-induced immune responses on disease severity remains unclear. Moreover, the efficacy of therapeutic interventions during hospitalisation requires further investigation. The study aims to analyse the clinical course of COVID-19 in hospitalised patients, taking into account SARS-CoV-2 variants, viral sequences, and the impact of different vaccines. The primary outcome is all-cause in-hospital mortality, while secondary outcomes include admission to intensive care unit and length of stay, duration of hospitalisation, and the level of respiratory support required. METHODS: This ongoing multicentre study observes hospitalised adult patients with confirmed SARS-CoV-2 infection, utilising a combination of retrospective and prospective data collection. It aims to gather clinical and laboratory variables from around 35,000 patients, with potential for a larger sample size. Data analysis will involve biostatistical and machine-learning techniques. Selected patients will provide biological material. The study started on October 14, 2021 and is scheduled to end on October 13, 2026. DISCUSSION: The analysis of a large sample of retrospective and prospective data about the acute phase of SARS CoV-2 infection in hospitalised patients, viral variants and vaccination in several European and non-European countries will help us to better understand risk factors for disease severity and the interplay between SARS CoV-2 variants, immune responses and vaccine efficacy. The main strengths of this study are the large sample size, the long study duration covering different waves of COVID-19 and the collection of biological samples that allows future research. TRIAL REGISTRATION: The trial has been registered on ClinicalTrials.gov. The unique identifier assigned to this trial is NCT05463380.

EuCARE-POSTCOVID Study: a multicentre cohort study on long-term post-COVID-19 manifestations.

BACKGROUND: Post-COVID-19 condition refers to persistent or new onset symptoms occurring three months after acute COVID-19, which are unrelated to alternative diagnoses. Symptoms include fatigue, breathlessness, palpitations, pain, concentration difficulties ("brain fog"), sleep disorders, and anxiety/depression. The prevalence of post-COVID-19 condition ranges widely across studies, affecting 10-20% of patients and reaching 50-60% in certain cohorts, while the associated risk factors remain poorly understood. METHODS: This multicentre cohort study, both retrospective and prospective, aims to assess the incidence and risk factors of post-COVID-19 condition in a cohort of recovered patients. Secondary objectives include evaluating the association between circulating SARS-CoV-2 variants and the risk of post-COVID-19 condition, as well as assessing long-term residual organ damage (lung, heart, central nervous system, peripheral nervous system) in relation to patient characteristics and virology (variant and viral load during the acute phase). Participants will include hospitalised and outpatient COVID-19 patients diagnosed between 01/03/2020 and 01/02/2025 from 8 participating centres. A control group will consist of hospitalised patients with respiratory infections other than COVID-19 during the same period. Patients will be followed up at the post-COVID-19 clinic of each centre at 2-3, 6-9, and 12-15 months after clinical recovery. Routine blood exams will be conducted, and patients will complete questionnaires to assess persisting symptoms, fatigue, dyspnoea, quality of life, disability, anxiety and depression, and post-traumatic stress disorders. DISCUSSION: This study aims to understand post-COVID-19 syndrome's incidence and predictors by comparing pandemic waves, utilising retrospective and prospective data. Gender association, especially the potential higher prevalence in females, will be investigated. Symptom tracking via questionnaires and scales will monitor duration and evolution. Questionnaires will also collect data on vaccination, reinfections, and new health issues. Biological samples will enable future studies on post-COVID-19 sequelae mechanisms, including inflammation, immune dysregulation, and viral reservoirs. TRIAL REGISTRATION: This study has been registered with ClinicalTrials.gov under the identifier NCT05531773.

One-year cognitive follow-up of COVID-19 hospitalized patients.

BACKGROUND AND PURPOSE: Cognitive dysfunction has been observed following recovery from COVID-19. To the best of our knowledge, however, no study has assessed the progression of cognitive impairment after 1 year. The aim was to assess cognitive functioning at 1 year from hospital discharge, and eventual associations with specific clinical variables. METHODS: Seventy-six patients (aged 22-74 years) who had been hospitalized for COVID-19 were recruited. Patients received neuropsychological assessments at 5 (n = 76) and 12 months (n = 53) from hospital discharge. RESULTS: Over half (63.2%) of the patients had deficits in at least one test at 5 months. Compared to the assessment at 5 months, verbal memory, attention and processing speed improved significantly after 1 year (all p < 0.05), whereas visuospatial memory did not (all p > 0.500). The most affected domains after 1 year were processing speed (28.3%) and long-term visuospatial (18.1%) and verbal (15.1%) memory. Lower PaO2 /FiO2 ratios in the acute phase were associated with worse verbal long-term memory (p = 0.029) and visuospatial learning (p = 0.041) at 5 months. Worse visuospatial long-term memory at 5 months was associated with hyposmia (p = 0.020) and dysgeusia (p = 0.037). CONCLUSION: Our study expands the results from previous studies showing that cognitive impairment can still be observed after 1 year. Patients with severe COVID-19 should receive periodic cognitive follow-up evaluations, as cognitive deficits in recovered patients could have social and occupational implications.

Anxiety and depression symptoms after virological clearance of COVID-19: A cross-sectional study in Milan, Italy.

Prevalence of anxiety or depression was investigated in 105 coronavirus disease 2019 (COVID-19) patients at 1 to 3 months from virological clearance by hospital anxiety and depression scale (HADS-A/D). 30% of patients displayed pathological HADS-A/D, 52.4% showed persistent symptoms. Pathological patients with HADS-A/D more commonly reported symptom persistence, even after adjustment for age, gender, and disease severity. Psychological assessments should be encouraged in COVID-19 patients' follow-up.

Long-term maintenance of virologic suppression in native and migrant HIV-1 naïve patients: an Italian cohort study.

Little is known about long-term maintenance of virologic suppression in HIV migrants in Italy. The study aims to compare virologic failure rates and associated factors among antiretroviral therapy (ART)-naïve migrants and natives enrolled in the ARCA database since 2007 who achieved virologic suppression within 18 months from the beginning of the ART. Kaplan-Meier method assessed the probability of virologic suppression and failure. Cox regression model was used for multivariate analysis. Of 2515 patients, 2020 (80.3%) were Italian, 286 (10.6%) migrants from low-income countries, of whom 201 (75.0%) from Africa, and 227 (9.0%) from high-income-countries. The median follow-up was 4.5 years (IQR 2.5-7). No difference was observed in the time of achievement of virological suppression in the three groups (log-rank: p = 0.5687). Higher probability of virologic failure was observed in Africans compared to Italians, to patients from high-income-countries and from low-income-countries other than Africans (Log-rank = p < 0.001). In the adjusted analysis, a higher virologic failure risk was found in Africans only compared to Italians. [HR 4.01; 95% CI 2.44-6.56, p < 0.001]. In Italy, African migrants are less likely to maintain virologic suppression compared to natives and other migrants. Targeted interventions could be needed for foreigners, especially for Africans.

Impact of psychological intervention on anxiety, depression, and post-traumatic stress disorder: results from a longitudinal study of hospitalized Covid-19 patients.

OBJECTIVE: Hospitalization for Covid-19 has been recognized as a potentially traumatic experience. This longitudinal cohort study assessed the impact of psychological intervention for Covid-19 patients on anxiety, depression, and post-traumatic stress disorder (PTSD). MATERIALS AND METHODS: Of 386 Covid-19 patients enrolled, 127 completed HADS and PCL-5 questionnaires at 2 months (T1), 6 months (T2) and 12 months (T3) after hospital discharge. Between T1 and T2, patients were offered the opportunity to receive psychological intervention: 92 did not request any psychological support (No support group), 15 received only one psychological consultation (Consultation group) and 20 received longer psychological support (Support group). Mixed ANOVAs were used to assess the psychological symptoms of the 3 Groups over Time. RESULTS: The No support group reported lower anxiety, depression, and PTSD than the other two groups. Anxiety and PTSD increased over time across groups. A Time x Group interaction was found for depression (F(2.124)=3.72, p<.05, pη2=.06). The Support group reported a decrease in depression from T1 (M=7.85) to T2 (M=7.05) and an increase from T2 to T3 (M=8.05), although not significant. The No support (T1 M=2.84; T3 M=4.36; p<.001) and the Consultation groups (T1 M=4.73; T3 M=6.33; p<.05) reported an increase in depression from T1 to T3. CONCLUSIONS: Psychological interventions were appropriately allocated to patients with more severe symptoms. Most of the patients did not request psychological intervention. Long-term psychological support may have helped Covid-19 patients to contain depressive symptoms over time.

Association between tight junction proteins and cognitive performance in untreated persons with HIV.

BACKGROUND: HIV-associated neurocognitive disorders (HAND) still affects persons with HIV (PWH) and their pathogenesis is not completely understood. We aimed to explore the association between plasma and cerebrospinal fluid (CSF) markers of blood-brain barrier (BBB) impairment and HAND in untreated PWH. DESIGN: Cross-sectional study. METHODS: We enrolled untreated PWH, who underwent blood examinations and lumbar puncture to measure inflammation (IL-15, TNF-α), BBB damage (zonulin and tight junction proteins, tight junction proteins: occludin, claudin-5) and endothelial adhesion molecules (VCAM-1, ICAM-1). A comprehensive neurocognitive battery was used to diagnose HAND (Frascati criteria). RESULTS: Twenty-one patients (21/78, 26.9%) patients presented HAND (100% ANI). HAND patients displayed more frequently non-CNS AIDS-defining conditions, lower nadir CD4 + T cells and increased CD4 + T-cell exhaustion (lower CD4 + CD127 + and CD4 + CD45RA + T-cell percentages), in comparison to individuals without cognitive impairment. Furthermore, HAND was characterized by higher plasma inflammation (IL-15) but lower CSF levels of biomarkers of BBB impairment (zonulin and occludin). The association between BBB damage with HAND was confirmed by fitting a multivariable logistic regression. CSF/plasma endothelial adhesion molecules were not associated with HAND but with a poor performance in different cognitive domains. CONCLUSION: By showing heightened inflammation and BBB impairment, our study suggests loss of BBB integrity as a possible factor contributing to the development of HAND in untreated PWH.

Clinical characteristics and outcomes of vaccinated patients hospitalised with SARS-CoV-2 breakthrough infection: Multi-IPV, a multicentre study in Northern Italy.

BACKGROUND: Despite the well-known efficacy of anti-COVID-19 vaccines in preventing morbidity and mortality, several vaccinated individuals are diagnosed with SARS-CoV-2 breakthrough infection, which might require hospitalisation. This multicentre, observational, and retrospective study aimed to investigate the clinical characteristics and outcomes of vaccinated vs. non-vaccinated patients, both hospitalised with SARS-CoV-2 infection in 3 major hospitals in Northern Italy. METHODS: Data collection was retrospective, and paper and electronic medical records of adult patients with a diagnosed SARS-CoV-2 infection were pseudo-anonymised and analysed. Vaccinated and non-vaccinated individuals were manually paired, using a predetermined matching criterion (similar age, gender, and date of hospitalisation). Demographic, clinical, treatment, and outcome data were compared between groups differing by vaccination status using Pearson's Chi-square and Mann-Whitney tests. Moreover, multiple logistic regression analyses were performed to assess the impact of vaccination status on ICU admission or intra-hospital mortality. RESULTS: Data from 360 patients were collected. Vaccinated patients presented with a higher prevalence of relevant comorbidities, like kidney replacement therapy or haematological malignancy, despite a milder clinical presentation at the first evaluation. Non-vaccinated patients required intensive care more often than their vaccinated counterparts (8.8% vs. 1.7%, p = 0.002). Contrariwise, no difference in intra-hospital mortality was observed between the two groups (19% vs. 20%, p = 0.853). These results were confirmed by multivariable logistic regressions, which showed that vaccination was significantly associated with decreased risk of ICU admission (aOR=0.172, 95%CI: 0.039-0.542, p = 0.007), but not of intra-hospital mortality (aOR=0.996, 95%CI: 0.582-1.703, p = 0.987). CONCLUSIONS: This study provides real-world data on vaccinated patients hospitalised with COVID-19 in Northern Italy. Our results suggest that COVID-19 vaccination has a protective role in individuals with higher risk profiles, especially regarding the need for ICU admission. These findings contribute to our understanding of SARS-CoV-2 infection outcomes among vaccinated individuals and emphasise the importance of vaccination in preventing severe disease, particularly in those countries with lower first-booster uptake rates.

Clinical Outcome and 7-Day Virological Clearance in High-Risk Patients with Mild-Moderate COVID-19 Treated with Molnupiravir, Nirmatrelvir/Ritonavir, or Remdesivir.

INTRODUCTION: We compared the effectiveness and virological clearance (VC) at day 7 (T7) post-treatment with molnupiravir, nirmatrelvir/ritonavir, and remdesivir in SARS-CoV-2-infected patients at high risk (HR) for clinical progression. METHODS: We conducted a retrospective study enrolling HR patients with mild-to-moderate COVID-19 (Jan-Oct 2022) treated with nirmatrelvir/ritonavir or molnupiravir or 3 days of remdesivir. We investigated clinical recovery at T7 (resolution of symptoms for ≥ 72 h or all-cause death), VC at T7 (PCR/antigenic negative nasopharyngeal swab), and median time to VC (days from symptom onset to the first negative swab). Factors associated with VC were investigated by logistic regression. RESULTS: In the study, 92/376 (43.8%) patients received molnupiravir, 150/376 (24.7%) nirmatrelvir/ritonavir, and 134/376 (31.5%) remdesivir. Forty-nine (13%) patients were unvaccinated or incompletely vaccinated. Patients treated with nirmatrelvir/ritonavir were younger and presented immunodeficiencies more frequently; remdesivir was used more commonly in patients hospitalized for other diseases. A high proportion of patients obtained clinical recovery without differences among the therapies (97.5% for molnupiravir, 98.3% for nirmatrelvir/ritonavir, and 93.6% for remdesivir); 12 (3.7%) patients died. Nirmatrelvir/ritonavir was associated with a higher proportion of T7 VC and a shorter time to VC compared to molnupiravir/remdesivir, also after adjustment for age and immunodeficiency (AOR 0.445 RDV vs. NMV-r, 95% CI 0.240-0.826, p = 0.010; AOR 0.222 MNP vs. NMV-r, 95% CI 0.105-0.472, p < 0.001). CONCLUSIONS: SARS-COV-2 antiviral treatments are an excellent therapeutic strategy in HR patients. Nirmatrelvir/ritonavir showed a higher proportion of VC as early as 7 days after treatment, confirming its likely superiority in indirect comparisons.

Nirmatrelvir-ritonavir, molnupiravir, and a 3-day course of remdesivir are antiviral therapies recommended in patients with a mild-to-moderate COVID-19 disease at high risk of clinical progression. Randomized controlled trials and observational studies have shown their efficacy in reducing all-cause mortality and clinical progression. Few data are available about a direct comparison among the three drugs; furthermore, the possible role of nirmatrelvir-ritonavir in increasing viral clearance and in reducing the duration of viral shedding needs to be further elucidated. We thus investigated the effectiveness, safety, and virological clearance 7 days after treatment with these three antivirals in our retrospective cohort. We included in the analysis patients that have received these treatments from January 2022 and October 2022; we observed that patients receiving nirmatrelvir-ritonavir displayed a shorter median time from symptoms' onset to virological clearance and a higher proportion of virological clearance at day 7, also after adjustment for possible confounders, compared to molnupiravir and remdesivir. Our data might help in understanding which COVID-19 patients may benefit mostly from antiviral therapies and in the choice of antiviral therapy.

In-hospital mortality during the wild-type, alpha, delta, and omicron SARS-CoV-2 waves: a multinational cohort study in the EuCARE project.

Background: Investigating outcomes of hospitalised COVID-19 patients throughout the pandemic is crucial to understand the impact of different SARS-CoV-2 variants. We compared 28-day in-hospital mortality of Wild-type, Alpha, Delta, and Omicron variant infections. Whether the difference in risk by variant varied by age was also evaluated. Methods: We conducted a cohort study including patients ≥18 years, hospitalised between 2020 and 02-01 and 2022-10-15 with a SARS-CoV-2 positive test, from nine countries. Variant was classified based on sequenced viruses or from national public metadata. Mortality was compared using the cumulative incidence function and subdistribution hazard ratios (SHR) adjusted for age, sex, calendar time, and comorbidities. Results were shown age-stratified due to effect measure modification (P < 0.0001 for interaction between age and variant). Findings: We included 38,585 participants: 19,763 Wild-type, 6387 Alpha, 3640 Delta, and 8795 Omicron. The cumulative incidence of mortality decreased throughout the study period. Among participants ≥70 years, the adjusted SHR (95% confidence interval) for Delta vs. Omicron was 1.66 (1.29-2.13). This estimate was 1.66 (1.17-2.36) for Alpha vs. Omicron, and 1.34 (0.92-1.95) for Wild-type vs. Omicron. These were 1.21 (0.81-1.82), 1.21 (0.68-2.17), and 0.98 (0.53-1.82) among unvaccinated participants. When comparing Omicron sublineages, the aSHR for BA.1 was 1.92 (1.43-2.58) compared to BA.2 and 1.52 (1.11-2.08) compared to BA.5. Interpretation: The herein observed decrease in in-hospital mortality seems to reflect a combined effect of immunity from vaccinations and previous infections, although differences in virulence between SARS-CoV-2 variants may also have contributed. Funding: European Union's Horizon Europe Research and Innovation Programme.

Development and validation of a prediction score for failure to casirivimab/imdevimab in hospitalized patients with COVID-19 pneumonia.

Introduction: Casirivimab and imdevimab (CAS/IMV) are two non-competing, high-affinity human IgG1 anti-SARS-CoV-2 monoclonal antibodies, that showed a survival benefit in seronegative hospitalized patients with COVID-19. This study aimed to estimate the day-28 risk of mechanical ventilation (MV) and death in individuals hospitalized for severe COVID-19 pneumonia and receiving CAS/IMV. Additionally, it aimed to identify variables measured at the time of hospital admission that could predict these outcomes and derive a prediction algorithm. Methods: This is a retrospective, observational cohort study conducted in 12 hospitals in Italy. Adult patients who were consecutively hospitalized from November 2021 to February 2022 receiving CAS/IMV were included. A multivariable logistic regression model was used to identify predictors of MV or death by day 28 from treatment initiation, and ß-coefficients from the model were used to develop a risk score that was derived by means of leave-one-out internal cross-validation (CV), external CV, and calibration. Secondary outcome was mortality. Results: A total of 480 hospitalized patients in the training set and 157 patients in the test set were included. By day 28, 36 participants (8%) underwent MV and 28 died (6%) for a total of 58 participants (12%) experiencing the composite primary endpoint. In multivariable analysis, four factors [age, PaO2/FiO2 ratio, lactate dehydrogenase (LDH), and platelets] were independently associated with the risk of MV/death and were used to generate the proposed risk score. The accuracy of the score in the area under the curve (AUC) was 0.80 and 0.77 in internal validation and test for the composite endpoint and 0.87 and 0.86 for death, respectively. The model also appeared to be well calibrated with the raw data. Conclusion: The mortality risk reported in our study was lower than that previously reported. Although CAS/IMV is no longer used, our score might help in identifying which patients are not likely to benefit from monoclonal antibodies and may require alternative interventions.

Cost analysis of dalbavancin versus standard of care for the treatment of acute bacterial skin and skin structure infections (ABSSSIs) in two Italian hospitals.

Objectives: Thanks to its long half-life, dalbavancin qualifies as an optimal drug for saving costs. We aimed to assess the cost and effectiveness of dalbavancin versus the standard of care (SoC). Patients and methods: We conducted a multicentre retrospective study, including all hospitalized or outpatients diagnosed with ABSSSIs at Padua University Hospital, Padua and San Paolo Hospital, Milan (1 January 2016 to 31 July 2020). We compared patients according to antibiotic treatment (dalbavancin versus SoC), the number of lines of dalbavancin treatment, and monotherapy or combination (dalbavancin in association with other antibiotics). Primary endpoints were direct medical costs and length of hospital stay (LOS) associated with ABSSSI management; Student's t-test, chi-squared test and one-way ANOVA were used. Results: One hundred and twenty-six of 228 (55.3%) patients received SoC, while 102/228 (44.7%) received dalbavancin. Twenty-seven of the 102 (26.5%) patients received dalbavancin as first-line treatment, 46 (45.1%) as second-line, and 29 (28.4%) as third- or higher-line treatment. Most patients received dalbavancin as monotherapy (62/102; 60.8%). Compared with SoC, dalbavancin was associated with a significant reduction of LOS (5 ±â€Š7.47 days for dalbavancin, 9.2 ±â€Š5.59 days for SoC; P < 0.00001) and with lower mean direct medical costs (3470 ±â€Š2768€ for dalbavancin; 3493 ±â€Š1901€ for SoC; P = 0.9401). LOS was also reduced for first-line dalbavancin, in comparison with second-, third- or higher-line groups, and for dalbavancin monotherapy versus combination therapy. Mean direct medical costs were significantly lower in first-line dalbavancin compared with higher lines, but no cost difference was observed between monotherapy and combination therapy. Conclusions: Monotherapy with first-line dalbavancin was confirmed as a promising strategy for ABSSSIs in real-life settings, thanks to its property in reducing LOS and saving direct medical costs.

SARS-CoV-2 mRNA Vaccine Response in People Living with HIV According to CD4 Count and CD4/CD8 Ratio.

BACKGROUND: Our aim was to estimate the rates of not achieving a robust/above-average humoral response to the COVID-19 mRNA vaccine in people living with HIV (PLWH) who received ≥2 doses and to investigate the role of the CD4 and CD4/CD8 ratio in predicting the humoral response. METHODS: We evaluated the humoral anti-SARS-CoV-2 response 1-month after the second and third doses of COVID-19 mRNA vaccine as a proportion of not achieving a robust/above-average response using two criteria: (i) a humoral threshold identified as a correlate of protection against SARS-CoV-2 (<90% vaccine efficacy): anti-RBD < 775 BAU/mL or anti-S < 298 BAU/mL, (ii) threshold of binding antibodies equivalent to average neutralization activity from the levels of binding (nAb titer < 1:40): anti-RBD < 870 BAU/mL or anti-S < 1591 BAU/mL. PLWH were stratified according to the CD4 count and CD4/CD8 ratio at first dose. Logistic regression was used to compare the probability of not achieving robust/above-average responses. A mixed linear model was used to estimate the mean anti-RBD titer at various time points across the exposure groups. RESULTS: a total of 1176 PLWH were included. The proportions of participants failing to achieve a robust/above-average response were significantly higher in participants with a lower CD4 and CD4/CD8 ratio, specifically, a clearer gradient was observed for the CD4 count. The CD4 count was a better predictor of the humoral response of the primary cycle than ratio. The third dose was pivotal in achieving a robust/above-average humoral response, at least for PLWH with CD4 > 200 cells/mm3 and a ratio > 0.6. CONCLUSIONS: A robust humoral response after a booster dose has not been reached by 50% of PLWH with CD4 < 200 cells mm3. In the absence of a validated correlate of protections in the Omicron era, the CD4 count remains the most solid marker to guide vaccination campaigns in PLWH.

Sarilumab plus standard of care vs standard of care for the treatment of severe COVID-19: a phase 3, randomized, open-labeled, multi-center study (ESCAPE study).

Background: Among interleukin-6 inhibitors suggested for use in COVID-19, there are few robust evidences for the efficacy of sarilumab. Herein, we evaluated the efficacy and safety of sarilumab in severe COVID-19. Methods: In this phase 3, open-labeled, randomized clinical trial, conducted at 5 Italian hospitals, adults with severe COVID-19 pneumonia (excluding mechanically ventilated) were randomized 2:1 to receive intravenous sarilumab (400 mg, repeatable after 12 h) plus standard of care (SOC) (arm A) or to continue SOC (arm B). Randomization was web-based. As post-hoc analyses, the participants were stratified according to baseline inflammatory parameters. The primary endpoint was analysed on the modified Intention-To-Treat population, including all the randomized patients who received any study treatment (sarilumab or SOC). It was time to clinical improvement of 2 points on a 7-points ordinal scale, from baseline to day 30. We used Kaplan Meier method and log-rank test to compare the primary outcome between two arms, and Cox regression stratified by clinical center and adjusted for severity of illness, to estimate the hazard ratio (HR). The trial was registered with EudraCT (2020-001390-76). Findings: Between May 2020 and May 2021, 191 patients were assessed for eligibility, of whom, excluding nine dropouts, 176 were assigned to arm A (121) and B (55). At day 30, no significant differences in the primary endpoint were found (88% [95% CI 81-94] in arm A vs 85% [74-93], HR 1.07 [0.8-1.5] in arm B; log-rank p = 0.50). After stratifying for inflammatory parameters, arm A showed higher probability of improvement than B without statistical significance in the strata with C reactive protein (CRP) < 7 mg/dL (88% [77-96] vs 79% [63-91], HR 1.55 [0.9-2.6]; log-rank p = 0.049) and in the strata with lymphocytes <870/mmc (90% [79-96]) vs (73% [55-89], HR 1.53 [0.9-2.7]; log-rank p = 0.058). Overall, 39/121 (32%) AEs were reported in arm A and 14/55 (23%) in B (p = 0.195), while serious AEs were 22/121 (18%) and 7/55 (11%), respectively (p = 0.244). There were no treatment-related deaths. Interpretation: The efficacy of sarilumab in severe COVID-19 was not demonstrated both in the overall and in the stratified for severity analysis population. Exploratory analyses suggested that subsets of patients with lower CRP values or lower lymphocyte counts might have had benefit with sarilumab treatment, but this finding would require replication in other studies. The relatively low rate of concomitant corticosteroid use, could partially explain our results. Funding: This study was supported by INMI "Lazzaro Spallanzani" Ricerca Corrente Linea 1 on emerging and reemerging infections, funded by Italian Ministry of Health.

Persistence of High Percentage of Peripheral Activated CD8+ T Cells Predict Cytologic HPV-Related Dysplasia in cART-Treated, HIV-Positive Subjects.

Background: People with HIV are at increased risk of human papillomavirus (HPV) disease progression, given the persistence of immune activation and residual inflammation despite effective combination antiretroviral therapy (cART). Whether a low CD4:CD8 T-cell ratio, known to mirror peripheral immune dysfunction, is associated with squamous intraepithelial lesions (SILs) is unknown. Methods: This was a retrospective cohort study on cART-treated HIV-positive subjects undergoing screening for HPV-related dysplasia (anal/cervical cytology and HPV genotyping). SIL was defined as the presence of either atypical squamous cells of undetermined significance (ASCUS), low-grade SILs, or high-grade SILs. Demographic and viro-immunological parameters (T-cell count, CD4:CD8 T-cell ratio, CD8+ CD38+ T-cell percentage) at the time of screening were analyzed by the chi-square test, Mann-Whitney test, and multivariate logistic regression analysis. Results: A total of 419 cART-treated subjects were included. Half of the patients had cervical/anal SIL. Individuals with SIL were more commonly males, were men who have sex with men, were coinfected with Treponema pallidum, had been treated with integrase inhibitor (INSTI)-based cART regimens, and had a shorter time since HIV diagnosis and cART initiation than subjects with normal cytology. CD38+ CD8+ T-cell percentage, but not the CD4:CD8 T-cell ratio, correlated with SILs. HPV infection, especially with multiple and high-risk genotypes, was confirmed to be associated with SIL. In multivariate analysis, the only factors independently associated with cervical/anal dysplasia were HPV infection and harboring higher percentages of peripheral activated CD38+ CD8+ T cells. Conclusions: HPV infection is the major driver of dysplasia in the setting of HIV infection. In this study, CD8+ CD38+ T cells were an independent predictor of dysplasia in cART-treated subjects, while CD4:CD8 T-cell ratio was not. In the setting of HIV-HPV coinfection, CD4:CD8 T-cell ratio may not fully capture the alterations of HPV-specific immunity.

Real World Estimate of Vaccination Protection in Individuals Hospitalized for COVID-19.

Whether vaccination confers a protective effect against progression after hospital admission for COVID-19 remains to be elucidated. Observational study including all the patients admitted to San Paolo Hospital in Milan for COVID-19 in 2021. Previous vaccination was categorized as: none, one dose, full vaccination (two or three doses >14 days before symptoms onset). Data were collected at hospital admission, including demographic and clinical variables, age-unadjusted Charlson Comorbidity index (CCI). The highest intensity of ventilation during hospitalization was registered. The endpoints were in-hospital death (primary) and mechanical ventilation/death (secondary). Survival analysis was conducted by means of Kaplan-Meier curves and Cox regression models. Effect measure modification by age was formally tested. We included 956 patients: 151 (16%) fully vaccinated (18 also third dose), 62 (7%) one dose vaccinated, 743 (78%) unvaccinated. People fully vaccinated were older and suffering from more comorbidities than unvaccinated. By 28 days, the risk of death was of 35.9% (95%CI: 30.1−41.7) in unvaccinated, 41.5% (24.5−58.5) in one dose and 28.4% (18.2−38.5) in fully vaccinated (p = 0.63). After controlling for age, ethnicity, CCI and month of admission, fully vaccinated participants showed a risk reduction of 50% for both in-hospital death, AHR 0.50 (95%CI: 0.30−0.84) and for mechanical ventilation or death, AHR 0.49 (95%CI: 0.35−0.69) compared to unvaccinated, regardless of age (interaction p > 0.56). Fully vaccinated individuals in whom vaccine failed to keep them out of hospital, appeared to be protected against critical disease or death when compared to non-vaccinated. These data support universal COVID-19 vaccination.

Female gender is associated with long COVID syndrome: a prospective cohort study.

OBJECTIVE: We explored the association between female gender and long COVID syndrome, defined as persistence of physical and/or psychological symptoms for more than 4 weeks after recovery from acute COVID-19 disease. The secondary aim was to identify predictors of long COVID syndrome by multivariable logistic regression analysis. METHODS: This was a single-centre prospective cohort study conducted at San Paolo Hospital in Milan, Italy. We enrolled adult patients who were evaluated at the post-COVID outpatient service of our Infectious Diseases Unit between 15 April 2020 and 15 December 2020. Participants were individuals who had clinically recovered from COVID-19 and in whom virological clearance had occurred. Previous infection by SARS-CoV-2 was microbiologically documented by positivity using a reverse-transcriptase polymerase chain reaction (RT-PCR) assay of nasopharyngeal swab. All enrolled patients underwent blood tests and a comprehensive medical examination at follow-up. Individuals were interviewed about resolved and persisting symptoms and were asked to fill in two questionnaires to allow assessment of the Hospital Anxiety and Depression symptoms (HADS) score and of the Impact of Event Scale-Revised (IES-R) score. RESULTS: A total of 377 patients were enrolled in the study. The median time from symtpom onset to virological clerance was 44 (37-53) days. A diagnosis of long COVID syndrome was made in 260/377 (69%) patients. The most common reported symptoms were fatigue (149/377, 39.5%), exertional dyspnoea (109/377, 28.9%), musculoskeletal pain (80/377, 21.2%) and "brain fog" (76/377, 20.2%). Anxiety symptoms were ascertained in 71/377 (18.8%) individuals, whereas 40/377 (10.6%) patients presented symptoms of depression. Post-traumatic stress disorder (defined by a pathological IES-R score) was diagnosed in one-third of patients (85/275, 31%). Female gender was independently associated with long COVID syndrome at multivariable analysis (AOR 3.3 vs. males, 95% CI 1.8-6.2, p < 0.0001). Advanced age (adjusted (A)OR 1.03 for 10 years older, 95% CI 1.01-1.05, p 0.01) and active smoking (AOR 0.19 for former smokers vs. active smokers, 95% CI 0.06-0.62, p 0.002) were also associated with a higher risk of long COVID, while no association was found between severity of disease and long COVID (AOR 0.67 for continuous positive airway pressure (CPAP)/non-invasive mechanical ventilation (NIMV)/orotracheal intubation (OTI) vs. no 02 therapy, 95% CI 0.29-1.55, p 0.85). DISCUSSION: Factors that were found to be associated with a higher risk of developing "long COVID" syndrome were female gender, older age and active smoking, but not severity of the acute disease. Individuals affected by SARS-CoV-2 infection with the aforementioned features should be early identified and involved in follow-up programmes.